Progression-free survival (PFS) rates were also 25% longer for patients in the ruxolitinib-containing arm at a HR of 0.75 (95% CI 0.52-1.10; P=0.14) than for capecitabine controls.

Median overall survival was 4.5 months in the ruxolitinib plus capecitabine group and 4.3 months in the placebo plus capecitabine group.

The probability of survival at 3, 6, and 12 months was 64%, 42%, and 22%, respectively, in the ruxolitinib plus capecitabine group.

This compared to 3, 6, and 12-month survival rates of 58%, 35%, and 11%, respectively, in the placebo plus capecitabine group.

In a prespecified subgroup of patients with a CRP level greater than the overall study population median (CRP >13 mg/L), overall survival was 53% greater at a HR of 0.47 (95% CI 0.26-0.85; P=0.011) for patients who received ruxolitinib plus capecitabine vs capecitabine alone.

Median overall survival in the elevated CRP subgroup was 2.7 months in the ruxolitinib plus capecitabine group vs. 1.8 months in the capecitabine alone group.

Progression-free survival was also 38% longer in the ruxolitinib-containing arm at a HR of 0.62 (95% CI 0.35-1.10; P=0.10) in the subgroup of patients with a CRP level greater than the median for the study population compared to the control arm.

"Multiple large studies have demonstrated a negative prognostic value for elevated markers of systemic inflammation in a wide variety of cancers [and] this effect is particularly strong in patients with pancreatic cancer including in the locally advanced, first-line and refractory settings," Herbert Hurwitz, MD, Duke University Medical Center, Durham, North Carolina and colleagues write in the Journal of Clinical Oncology.

"Results from this study support the potential clinical benefit of targeting JAK/STAT signaling with the JAK1/JAK2 inhibitor ruxolitinib."

A total of 127 patients with metastatic pancreatic adenocarcinoma with measurable or evaluable disease were assigned to either ruxolitinib, 15 mg, twice a day, on days 1 through 21 plus capecitabine, 10,000 mg/m2 twice a day, on days 1 through to 14 of a 21-day cycle or to placebo plus capecitabine given at the same dose and the same schedule.

For patients with an mGPS of 1 or 2 (CRP>10 mg/L), overall survival was 40% greater at a HR of 0.60 (95% CI 0.35-1.03; P=0.063), while for patients with an mGPS of 0 (CSRP ≤10 mg/L), the HR was 0.91 (95% CI 0.46-1.74; P=0.77).

"In the ITT (intent-to-treat) population and the CRP subgroups, more patients treated with ruxolitinib plus capecitabine experienced reductions in the sum of their target lesion tumor burden," investigators observe.

The overall response rate was 7.8% for patients who received additional ruxolitinib compared with 1.6% for those who received placebo plus capecitabine.

Disease control -- defined as stable disease or better -- was achieved by 26 patients or 40.6% in the ITT population receiving additional ruxolitinib vs. 23 patients or 36.5% in the placebo/capecitabine group.

Among patients with CRP >13 mg/L, the overall response rate was 6.5% for those who received additional ruxolitinib vs. 3.4% for capecitabine alone.

Disease control in the same subgroup of patients was achieved in 35.5% of patients in the ruxolitinib group vs. 20.7% of the comparator group.

A total of eight patients in the additional ruxolitinib group achieved a clinical benefit response compared with one patient in the control group and more patients with a CRP >13 mg/L treated with JAK1/JAK 2 inhibition similarly achieved a clinical benefit response than those who did not receive ruxolitinib.

Seven patients who received ruxolitinib plus capecitabine and 12 patients who received placebo plus capecitabine experienced an adverse event (AE) of any grade that led to discontinuation of the study drug.

However, grade 3 or greater AEs occurred with similar frequency between treatment groups. Nonhematologic grade 3 or greater AEs that occurred more frequently in the additional ruxolitinib arm included stomatitis, pneumonia, and pulmonary embolism.

Anemia was the most common hematologic AE in ruxolitinib-treated patients.

Limitations of the study include the fact that the benefits of ruxolitinib were primarily seen in the prespecified subgroup of patients with elevated CPR levels and only modest activity was observed from JAK1/JAK2 inhibition in the ITT population.

This was also only a proof-of-concept study with a limited sample size.

Nevertheless, investigators concluded that their results "support the importance of cytokine signaling and JAK/STAT signaling in pancreatic cancer and highlight the potential role of JAK inhibition as a novel therapeutic strategy for these patients."

Asked to comment on the study, Andrew KO, MD, University of California San Francisco School of Medicine, told MedPage Today that JAK1/JAK 2 inhibitor may be a promising new avenue, specifically for pancreatic cancer patients who have significant constitutional symptoms, notably wasting and cachexia, that can be attributed in part to a high level of systemic inflammation.

"In this clinical trial, inflammation was reflected by elevated serum levels of CRP which may prove to be a relatively straightforward biomarker that could be used to select patients most likely to benefit from treatment with ruxolitinib," Dr. Ko said in written correspondence.

"And if a similar benefit is confirmed in on-going larger, randomized phase III trials, it would provide important proof of principle that survival in these patients may be extended not only through controlling the size and growth of the tumor but also through ameliorating the symptoms of cachexia and inanition that so many with this disease experience."

Jacqueline Bromberg, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, New York, told MedPage Today pointed out that as a class, the JAK inhibitors have limited single agent activity in solid tumors.

"However, they have been shown to enhance the effectiveness of standard and targeted chemotherapies in pre-clinical models of solid tumors including pancreatic cancer," Dr. Bromberg said in written correspondence.

Mechanistically, this may be due to remodeling of the tumor microvasculature enhancing drug delivery, she added.

"Thus, the modest advantage of ruxolitinib given with capecitabine in this clinical trial may be due to the relative 'ineffectiveness' of capecitabine in pancreatic cancer," Dr. Bromberg noted.

"That said, one patient with elevated CRP was alive after 16 months on combination ruxolitinib/capecitabine so with the ongoing phase III trial, we are hopeful that more patients will have sustained benefit with combination therapy."

Hurwitz reports receiving honoraria from Genetech and ImClone Systems. He has served as a consultant or in an advisory role for a number of pharmaceutical companies including Genentech, Bristol-Myers Squibb, Sanofi, and Eli Lilly and he has also received research funding from Genentech, GlaxoSmithKline, Novartis, TRACON Pharmaceuticals, and Incyte Corporation.

Ko sits on the Data Safety Monitoring Board for InCyte for their current phase III trial of ruxolitinib in pancreatic cancer.

Bromberg disclosed no relationships with industry.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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